Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects both sexes, with a higher prevalence in women. Declining estrogen levels after menopause may render estrogen target neurons in the brain more susceptible to age or disease-related processes such as AD. To investigate the role of two single nucleotide polymorphisms in the first intron of the ER-alpha gene, denominated PvuII and XbaI, and their interaction with the known AD susceptibility gene APOE, we examined 131 patients with sporadic AD and 109 healthy control subjects. In multinomial logistic regression analysis, a significantly increased risk of sporadic AD because of interaction between the ER-alpha p allele and APOE epsilon4 allele was observed in women, taking subjects who had neither the p allele nor epsilon4 as reference [odds ratio (OR) 7.24; 95% CI, 2.22-23.60]. For women carrying the ER-alpha x allele together with APOE epsilon4, the risk of sporadic AD was similarly elevated (OR 8.33; 95% CI, 1.73-40.06). The data suggest that the p and x alleles of polymorphic ER-alpha gene interact synergistically with the APOE epsilon4 allele to increase the risk of AD in women but not in men in this Italian cohort.